Preparation of granular vitamin a esters

ABSTRACT

Process for the preparation of granular vitamin A esters by contacting the molten vitamin A esters with a cold organic liquid kept in motion.

United States Patent [151 3,682,989 Reif et al. 45 A 8, 1972 [54]PREPARATION OF GRANULAR VITAMIN A ESTERS [56] References Cited [72]Inventors: Werner Reif, Frankenthal; Axel UNITED STATES PATENTSNuerrenbach, Gruenstadt; Herwig Freyschlag, L d i h f all f 2,790,0174/1957 Lang et al ..260/674 Germany 2,886,603 5/1959 Shelton ..260/6453,017,668 1/1962 Sundman ..18/47.2 [73] Assrgnee: Badlsche Alllllll- &Soda-Fabnk Aktiengesellschaft, Ludwigshafen/ primary Examiner bewis GongRhme Germany Assistant Examiner-Diana G. Rivers 22 i il 24 1970Attorney-Johnston, Root, OKeeffe, Keil, Thompson & Shurtleff [21] Appl.No.: 31,790

[57] ABSTRACT [52] U.S.Cl ..260/410, 260/488 A, 260/499, process for thepreparation f granular vitamin A 260/3985 esters by contacting themolten vitamin A esters with [51] Int. Cl ..C07c 175/00 a cold Organicliquid kept in motion [58] Field of Search..260/4l0, 488 A, 704, 707,499;

424/344 10 Claims, No Drawings PREPARATION OF GRANULAR VITAMIN A ESTERSThis invention relates to a process for preparing granular vitamin Aesters which are easy to handle and substantially stable to mechanicalstresses and chemical action.

Vitamin A esters, which are the most important vitamin A derivatives(particularly vitamin A acetate and vitamin A palmitate), are usuallymarketed as formulations with organic solvents, such as vegetable oils,since the consistency of the pure substances makes it very difficult toprocess them into a form which is substantially free from foreignmatter, easy to handle, and mechanically and chemically stable.

It is an object of this invention to provide a process for thepreparation of a form of vitamin A esters which does not have thedrawbacks of prior art formulations.

This object is achieved and granules of vitamin A esters havingexcellent properties are obtained by introducing a melt of the vitamin Aester into a moving organic liquid cooled to from l to 70 C in which thevitamin A ester is insoluble at room temperature and which has a lowerdensity than the vitamin A ester, separating the resultant granules from.the liquid and drying them.

Vitamin A esters suitable for the process according to this inventionare those of monocarboxylic acids having from 2 to 18 carbon atoms,particularly the acetate and palmitate.

Suitable organic liquids are those whose density is lower than that ofthe vitamin A esters. The difference in density should be at least 0.02g/cm preferably at least 0.1 g/cm. Examples of suitable liquids arelower aliphatic alcohols having from 1 to 4 carbon atoms and gasolineshaving a boiling range of from 150 to 180 C.

Alcohols such as methanol, ethanol, isopropanol and n-butanol andmixtures of these alcohols are particularly suitable as liquids for usein accordance with this invention. Methanol is preferred.

The process may be carried out for example by allowing the vitamin Aester heated to a few degrees, preferably 3 to C, above its meltingpoint to drip or slowly flow through a tube into the cold liquid, whichhas a temperature of from -l0 to 70 C, preferably 25 to 50C. The outletof the tube may be situated beneath the surface of the liquid; in thiscase the depth of immersion has to correlated to the temperature of thevitamin A ester melt and the temperature of the cold liquid.

In order to ensure that the melt is always contacted with cold liquid,the liquid must be kept in motion. Thus the process may be carried outby introducing the melt into a tube through which the cold liquid ispassed. It is also possible to achieve the desired effect by stirring,provided the melt is added slowly.

The granules are advantageously dried in an inert-gas atmosphere, e.g.,under nitrogen or argon.

The granules prepared in accordance with this invention have a meanparticle size of from 2 to 8 mm.

If the process is to be carried out continuously, the granules formedmay for example be discharged from the liquid by means of a strainerbelt and then treated as usual. It is advantageous to carry out not onlythe drying operation but also all other operations in the absence ofoxygen, e.g., under an atmosphere of inert gas such as nitrogen orargon.

The granules obtained by the process according to this invention arespherical or of a flat oval shape, have a crystalline structure andexhibit unexpectedly high resistance to pressure and abrasion so thatthey can be poured without being damaged and, in particular be providedin this form with protective coatings of, for example, gelatin orpolyvinylpyrrolidone. It should also be pointed out that the granulesare free from occlu-w EXAMPLE 1 A melt of vitamin A acetate is drippedfrom a dropping funnel having an outlet 1 mm in diameter and heated at+65C into methanol at -45C. The methanol vessel is filled to a height of400 mm and the distance between the outlet of the funnel and themethanol surface is 5 mm. The drops of vitamin A acetate crystallizecompletely while sinking to the bottom of the vessel. The granulesformed are separated from the methanol, for example by suctionfiltration, and then dried in a stream of nitrogen. The granules arespherical in shape and have a diameter of about 3 to 4 mm.

Granules having the same properties are obtained when using ethanol,isopropanol or kerosine (boiling range to C) instead of methanol EXAMPLE2 A melt of vitamin A palmitate is dripped from a dropping funnel havingan outlet 2.5 mm in diameter and heated at 50C into methanol at 60C. Themethanol vessel is filled to a height of 400 mm and the distance betweenthe outlet of the funnel and the surface of the methanol is 10 mm.

The vitamin A palmitate solidifies into granules of flat oval shapehaving a diameter of about 5 to 6 mm. The granules are separated fromthe methanol and dried at 15C in a current of nitrogen.

EXAMPLE 3 A melt of vitamin A acetate is dripped from a dropping funnelhaving an outlet 1 mm in diameter and heated at +65C into methanol at40C at a rate of 60 drops per minute. A belt conveyor having a length of600 mm is immersed in the methanol to the extent of two thirds of itslength. At the point where the melt is dripped into the methanol thedistance between the belt and the surface of the methanol is 280 mm. Thesolidified and crystallized drops of vitamin A acetate are discharged bymeans of the belt conveyor and predried with nitrogen. On leaving thebelt the granular material still contains 10 percent by weight ofmethanol, but it does not stick together. It is then completely freedfrom methanol in a current of nitrogen. The granules obtained arespherules having a weight of about 30 to 40 mg.

We claim:

1. A process for preparing granular vitamin A esters comprisingintroducing molten vitamin A ester into a chilled liquid organic solventin which the vitamin A ester is insoluble at room temperature, saidsolvent having a temperature of l to 70C, said solvent having a densityat least 0.02 g/cm lower than the density of said vitamin A ester saidsolvent being kept in motion to always ensure contact between the meltand the chilled liquid solvent to form therein granules of said vitaminA ester, separating the resulting granules from the solvent and dryingthem.

2. A process for preparing granular vitamin A esters of aliphaticcarboxylic acids having two to 18 carbon atoms, comprising introducingthe molten vitamin A ester having a temperature which is 3 to 10C higherthan its melting point, into a stirred or flowing chilled organicsolvent being a member selected from the group consisting of loweraliphatic alcohols having one to four carbon atoms, mixtures thereof andgasolines boiling at a temperature of from 150 to 180C, in which thevitamin A ester is insoluble at room tempera ture, at a temperature offrom 25 and 50C, said solvent having a lower density than the vitamin Aester, the difference in density being 0.02 g/cm or more, separating theresulting granules from the solvent and drying them, said process beingcarried out in an inertgas atmosphere.

3. A process for preparing granular vitamin A esters of aliphaticcarboxylic acids having two to 18 carbon atoms comprising introducingthe molten vitamin A ester having a temperature which is 3 to 10Chigher, than its melting point into a stirred or flowing chilled organicsolvent being member selected from the group consisting of loweraliphatic alcohols having one to four carbon atoms, mixtures thereof andgasolines boiling at a temperature of from 150 to 180C, in which thevitamin A ester is insoluble at room temperature, at a temperature offrom 25 to 5 0C, said solvent having a lower density than the vitamin Aester, the difference in density being 0.1 g/cm or more, separating theresulting granules from the solvent and drying them, said process beingcarried out in an inert-gas atmosphere.

4. A process for preparing granular vitamin A esters of aliphaticcarboxylic acids having two to 18 carbon atoms, comprising introducingthe molten vitamin A ester having a temperature which is 3 to C higherthan its melting point, into a stirred or flowing, chilled organicsolvent being a member selected from the group consisting of methanol,ethanol, isopropanol, nbutanol, mixtures thereof and gasolines boilingat a temperature of from 150 to 180C, in which the vitamin A ester isinsoluble at room temperature, at a temperature of from and 50C, saidsolvent having a lower density than the vitamin A ester, the differencein density being 0.1 g/cm or more, separating the resulting granulesfrom the solvent and drying them, said process being carried out in aninert-gas atmosphere.

5. A process for preparing granular vitamin A esters of aliphaticcarboxylic acids having two to 18 carbon atoms comprising introducingthe molten vitamin A ester having a temperature which is 3 to 10C higherthan its melting point, into a stirred or flowing chilled organicsolvent being a member selected from the group consisting of loweraliphatic alcohols having one to four carbon atoms, mixtures thereof andgasolines boiling at a temperature of from to C, in which the vitamin Aester is insoluble at room temperature, at a temperature of from 25 and50C, said solvent having a lower density then the vitamin A ester, thedifference in density being O. l g/cm or more, the molten ester beingintroduced directly beneath the surface of the solvent, separating theresulting granules from the solvent and drying them, said process beingcarried out in an inert gas atmosphere.

6. A process for preparing granular vitamin A esters of aliphaticcarboxylic acids having two to 18 carbon atoms comprising introducingthe molten vitamin A ester containing 0.1 to 5 percent of ananti-oxidant and having a temperature which is 3 to 10C higher than itsmelting point, into a stirred or flowing chilled organic solvent being amember selected from the group consisting of lower aliphatic alcoholshaving one to four carbon atoms, mixtures thereof and gasolines boilingat a temperature of from 150 to 180C, in which the vitamin A ester isinsoluble at room temperature, at a temperature of from 25 and 50C, saidsolvent having a lower density than the vitamin A ester, the differencein density being 0.1 g/cm or more, separating the resulting granulesfrom the solvent and drying them, said process being performed in aninert-gas atmosphere.

7. A process for preparing granular vitamin A esters of aliphaticcarboxylic acids having two to 18 carbon atoms, comprising introducingthe molten vitamin A ester having a temperature which is 3 to 10C higherthan its melting point, into a stirred or flowing chilled organicsolvent being a member selected from the group consisting of loweraliphatic alcohols having one to four carbon atoms, mixtures thereof andgasolines boiling at a temperature of from 150 to 180C, in which thevitamin A ester is insoluble at room temperature, at a temperature offrom 25 and 50C, said solvent having a lower density than the vitamin Aester, the difference in density being 0.02 g/cm or more, separating theresulting granules from the solvent and drying them, said granuleshaving diameters of 2 to 8 mm.

8. A process for preparing granular vitamin A esters of aliphaticcarboxylic acids having two to 18 carbon atoms comprising introducingthe molten vitamin A ester having a temperature which is 3 to 10C higherthan its melting point, into a stirred of flowing chilled organicsolvent being a member selected from the group consisting of loweraliphatic alcohols having one to four carbon atoms, mixtures thereof andgasolines boiling at a temperature of from 150 to 180C, in which thevitamin A ester is insoluble at room temperature, at a temperature offrom 25 and 50C, said solvent having a lower density than the vitamin Aester, the difference in density being 0.02 g/cm or more, separating theresulting granules from the solvent by a continuous method and dryingthem, said process being carried out in an inert-gas atmosphere.

9. A process for preparing granular vitamin A acetate comprisingintroducing the molten vitamin A acetate into stirred or flowing chilledmethanol at a temperature of from 25 and 50C, separating the resultinggranules from the solvent and drying them,

said process being carried out in an inert-gas atmosphere.

10. A process for preparing granular vitamin A palmitate comprisingintroducing the molten vitamin A palmitate into stirred or flowingchilled methanol at a 5

2. A process for preparing granular vitamin A esters of aliphaticcarboxylic acids having two to 18 carbon atoms, comprising introducingthe molten vitamin A ester having a temperature which is 3* to 10*Chigher than its melting point, into a stirred or flowing chilled organicsolvent being a member selected from the group consisting of loweraliphatic alcohols having one to four carbon atoms, mixtures thereof andgasolines boiling at a temperature of from 150* to 180*C, in which thevitamin A ester is insoluble at room temperature, at a temperature offrom -25 and -50*C, said solvent having a lower density than the vitaminA ester, the difference in density being 0.02 g/cm3 or more, separatingthe resulting granules from the solvent and drying them, said processbeing carried out in an inert-gas atmosphere.
 3. A process for preparinggranular vitamin A esters of aliphatic carboxylic acids having two to 18carbon atoms comprising introducing the molten vitamin A ester having atemperature which is 3* to 10*C higher, than its melting point into astirred or flowing chilled organic solvent being member selected fromthe group consisting of lower aliphatic alcohols having one to fourcarbon atoms, mixtures thereof and gasolines boiling at a temperature offrom 150* to 180*C, in which the vitamin A ester is insoluble at roomtemperature, at a temperature of from -25* to -50*C, said solvent havinga lower density than the vitamin A ester, the difference in densitybeing 0.1 g/cm3 or more, separating the resulting granules from thesolvent and drying them, said process being carried out in an inert-gasatmosphere.
 4. A process for preparing granular vitamin A esters ofaliphatic carboxylic acids having two to 18 carbon atoms, comprisingintroducing the molten vitamin A ester having a temperature which is 3*to 10*C higher than its melting point, into a stirred or flowing,chilled organic solvent being a member selected from the groupconsisting of methanol, ethanol, isopropanol, n-butanol, mixturesthereof and gasolines boiling at a temperature of from 150* to 180*C, inwhich the vitamin A ester is insoluble at room temperature, at atemperature of from -25* and -50*C, said solvent having a lower densitythan the vitamin A ester, the difference in density being 0.1 g/cm3 ormore, separating the resulting granules from the solvent and dryingthem, said process being carried out in an inert-gas atmosphere.
 5. Aprocess for preparing granular vitamin A esters of aliphatic carboxylicacids having two to 18 carbon atoms comprising introducing the moltenvitamin A ester having a temperature which is 3* to 10*C higher than itsmelting point, into a stirred or flowing chilled organic solvent being amember selected from the group consisting of lower aliphatic alcoholshaving one to four carbon atoms, mixtures thereof and gasolines boilingat a temperature of from 150* to 180*C, in which the vitamin A ester isinsoluble at room temperature, at a temperature of from -25* and 50*C,said solvent having a lower density then the vitamin A ester, thedifference in density being 0.1 g/cm3 or more, the molten ester beingintroduced directly beneath the surface of the solvent, separating theresulting granules from the solvent and drying them, said process beingcarried out in an inert gas atmosphere.
 6. A process for preparinggranular vitamin A esters of aliphatic carboxylic acids having two to 18carboN atoms comprising introducing the molten vitamin A estercontaining 0.1 to 5 percent of an anti-oxidant and having a temperaturewhich is 3* to 10*C higher than its melting point, into a stirred orflowing chilled organic solvent being a member selected from the groupconsisting of lower aliphatic alcohols having one to four carbon atoms,mixtures thereof and gasolines boiling at a temperature of from 150* to180*C, in which the vitamin A ester is insoluble at room temperature, ata temperature of from -25 and -50*C, said solvent having a lower densitythan the vitamin A ester, the difference in density being 0.1 g/cm3 ormore, separating the resulting granules from the solvent and dryingthem, said process being performed in an inert-gas atmosphere.
 7. Aprocess for preparing granular vitamin A esters of aliphatic carboxylicacids having two to 18 carbon atoms, comprising introducing the moltenvitamin A ester having a temperature which is 3* to 10* C higher thanits melting point, into a stirred or flowing chilled organic solventbeing a member selected from the group consisting of lower aliphaticalcohols having one to four carbon atoms, mixtures thereof and gasolinesboiling at a temperature of from 150* to 180*C, in which the vitamin Aester is insoluble at room temperature, at a temperature of from -25*and -50* C, said solvent having a lower density than the vitamin Aester, the difference in density being 0.02 g/cm3 or more, separatingthe resulting granules from the solvent and drying them, said granuleshaving diameters of 2 to 8 mm.
 8. A process for preparing granularvitamin A esters of aliphatic carboxylic acids having two to 18 carbonatoms comprising introducing the molten vitamin A ester having atemperature which is 3* to 10*C higher than its melting point, into astirred of flowing chilled organic solvent being a member selected fromthe group consisting of lower aliphatic alcohols having one to fourcarbon atoms, mixtures thereof and gasolines boiling at a temperature offrom 150* to 180*C, in which the vitamin A ester is insoluble at roomtemperature, at a temperature of from -25* and -50*C, said solventhaving a lower density than the vitamin A ester, the difference indensity being 0.02 g/cm3 or more, separating the resulting granules fromthe solvent by a continuous method and drying them, said process beingcarried out in an inert-gas atmosphere.
 9. A process for preparinggranular vitamin A acetate comprising introducing the molten vitamin Aacetate into stirred or flowing chilled methanol at a temperature offrom -25* and -50*C, separating the resulting granules from the solventand drying them, said process being carried out in an inert-gasatmosphere.
 10. A process for preparing granular vitamin A palmitatecomprising introducing the molten vitamin A palmitate into stirred orflowing chilled methanol at a temperature of from -25* and -50*C,separating the resulting granules from the solvent and drying them, saidprocess being carrying out in an inert-gas atmosphere.